CN106138071A - Ribose is for the purposes in the first reaction of acute myocardial infarction - Google Patents

Ribose is for the purposes in the first reaction of acute myocardial infarction Download PDF

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CN106138071A
CN106138071A CN201610602300.6A CN201610602300A CN106138071A CN 106138071 A CN106138071 A CN 106138071A CN 201610602300 A CN201610602300 A CN 201610602300A CN 106138071 A CN106138071 A CN 106138071A
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ribose
patient
reaction
intravenous
patients
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J.A.圣塞尔
D.J.佩尔科夫斯基
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Bioenergy Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention relates to ribose for the purposes in the first reaction of acute myocardial infarction.During the first reaction nursing, D ribose is administered to the patient suffering from acute myocardial infarction, in order to prevention heart damage.In those patients that can absorb fluid, the D ribose of Orally administered 2 to 5 grams.In the patient that can not absorb fluid or in the patient with venous access, use pyrogen-free D ribose with the 50 speed intravenouss of 300mg/kg/ hour.

Description

Ribose is for the purposes in the first reaction of acute myocardial infarction
The application be international filing date be the International Application Serial No. PCT/US2009/002074 on April 2nd, 2009 enter China, The invention of entitled " ribose is for the purposes in the first reaction of acute myocardial infarction " of Application No. 200980158527.4 The divisional application of patent application.
Related application
The application relate on April 2nd, 2008 submit to U.S. Provisional Patent Application Serial No. 61/072,772 and 2009 1 The U.S. Provisional Patent Application Serial No. 61/204,658 months 9 days submitted to also requires its priority.
Technical field and background technology
Known pentose ribose is important as the component of adenosine triphosphate (ATP) and nucleic acid in energy circulation.Also public Know that ribose only finds with low concentration in meals, and further, in many tissues, body produces the generation of ribose by it Journey of apologizing for having done sth. wrong i.e. pentose phosphate pathway is speed limit.
Known when using five days after removing cross clamp, ribose improves the healthy Cor Canitis standing global ischemia under normal body temperature Dirty recovery.Have discovered that (U.S. Patent number 6,159,942) before these inventors, use ribose enhancing and do not stand to lack Energy in the experimenter of blood injury.In the case of human patients, after occurring in hospital to heart attack patients, carry out the heart During dirty surgical operation, situation and the general health state of heart are the most impaired.After myocardial ischemia, especially in acute risk Interim, M & M increases.
Due to many factors, may occur in which abnormal heart function.All following factors all can negatively affect any medical science or Surgical result.Obviously, tissue die facilitates the loss of cardiac muscle of living, and it finally affects myocardial function.Factor such as preload, after Load, heart rate and the rhythm of the heart also affect cardiac output state.The commonly provided volume load and the medicament affecting afterload state.So And, heart rate and cardiac rhythm are the most intrinsic, and are not generally adjusted helping to correct any exception.
Health also contributes to this physiology's compromise state of heart.Such as, the blood of muscle infraction is developed into potentially In pipe, include that endarterial grumeleuse can severely impact cardiac function subsequently in any patient.Heart attack is helped to suffer from First reaction of person can be emergency medicine technical staff, ambulance personnel, hospital reception staff or clinic personnel.Suffer from arriving Start venous access (intravenous line) during person immediately, give one or two 350mg aspirin tablet and nitrate Or other vasodilator.Under with and without intubating, oxygen channel is placed on appropriate location.Temporary care relates to using this Occlusive grumeleuse is dissolved in the medicament of sample such as streptokinase, urokinase and tissue plasminogen activator (TPA), in order to obtain ischemia Alleviate immediately and original stable patient.This situation is generally found from the patient suffering from acute myocardial infarction (AMI).At this antithrombotic Interim, cardiac function can be and be typically instability.Until improving cardiac muscle unstability and dysfunction, Ke Yifa The M & M now increased.It is important for stablizing cardiac muscle the most immediately, and continues thereafter with stable and functional cardiac muscle Recovery is also the target of arbitrary therapy.
Need nonetheless remain for stablizing MI patient immediately when the first reaction so that myocardial stability can be recovered with function thus to be permitted The method being permitted surgical operation (if having indication).
Summary of the invention
Have been found that using D-ribose will assist in and stablize heart after AMI, intervene until other can be carried out.If Patient can absorb fluid, then prepare 3% solution and sipped by patient, until intake of at least 10 grams at least 1 hour period Ribose.Continue to use ribose at least one day.When patient carries out intravenous (IV) instillation, pyrogen-free D-ribose can be added Enter in transfusion.Preferably dosage of ribose is that intravenous uses 50-300mg/kg/ hour.Most preferably dosage of ribose is 200mg/kg/hr.Most preferably, using dextrose or the 5%w/v dextrose of equimolar amounts altogether to patient, it is with ribose simultaneously Give.
Continuation is oral or IV uses ribose, until patient has obtained a certain degree of cardiac muscle and stablized.For some patient, no Surgical operation must be carried out.For selecting to carry out those patients of CABG, to O ff-pump heart bypass Coronary Artery Bypass (off-pump Cardiac bypass grafting, OCBPG) concern increased.
If there being post operation, when patient is prepared for carrying out surgical operation, by MgSO4Join IV to instil In, until having given patient the MgSO of initial 5 grams4, preferably give with injecting of 100cc.At surgery intra-operative with outer Section's Post operation first 24 hours, level monitoring is to keep 2.5 equivalent parts per millions (meq/l) concentration.By potassium cationic carefully Maintain 4meq/l.Preferably, IV uses Milrinone (milronine) (Primacor, the Sanofi-of 0.5mcg/kg/min Aventis, Bridgeport, CT).
Disclose the purest, the preparation method of apyrogeneity ribose being suitable to that intravenous uses.Every kind of medicament or multiple It is 30 to 300mg/kg/ hour that the intravenous of medicament gives dosage, the aqueous solution of the apyrogeneity D-ribose of 5 to 30%w/v pass Send.When, in time jointly using D-Glucose, it can be delivered by the aqueous solution of the D-Glucose of 5 to 30%w/v.By to be administered One or more medicaments tap into venous access, and flowing is set as delivering one or more medicines of 30 to 300mg/kg/ hour Agent.Most preferably, using apyrogeneity D-ribose together with D-Glucose, it is each passed with the speed intravenous of 200mg/kg/ hour Send.When one or more medicaments Orally administered, the D-ribose of 1 to 20 gram is mixed in the water of 200ml, and picked-up every day 1 to 4 time.Most preferably, by soluble in water for the D-Glucose of the D-riboses of 5 grams and 5 grams, and 4 times are absorbed every day.
Patient in intensive care unit (ICU) uses as single medicament or more preferably joins with D-Glucose The apyrogeneity D-ribose closed.Retention period in ICU, intravenous uses one or more medicaments.Every kind of medicament or various medicaments Intravenous dosages to be administrated be 30 to 300mg/kg/ hour, by the apyrogeneity D-ribose of 5 to 30%w/v aqueous solution deliver. When, in time jointly using D-Glucose, it can be delivered by the aqueous solution of the D-Glucose of 5 to 30%w/v.By to be administered one Kind or various medicaments additionally tap into venous access, and flowing is set as delivering 30 to 300mg/kg/ hour one or more Medicament.Most preferably, using pyrogen-free D-ribose together with D-Glucose, it is each with the rate-delivery of 100mg/kg/ hour. When patient leaves ICU, it is useful for continuing to use one or more medicaments.When indwelling IV passage, continuation intravenous is executed With.When one or more medicaments Orally administered, the D-ribose of 1 to 20 gram is mixed in the water of 200ml, and picked-up every day 1 to 4 time.Most preferably, by soluble in water for the D-Glucose of the D-riboses of 5 grams and 5 grams, and 4 times are absorbed every day.
Detailed description of the invention
Provide the most following embodiment is implemented with the display present invention or how to be implemented.In the essence without departing substantially from the present invention In the case of god and scope, the method for the present invention can be made unsubstantiality with composition by those skilled in the art easily Change.In particular, it is noted that in most embodiments, it is proposed that D-ribose gives jointly with D-Glucose.It should be noted that and use D-Glucose is advised not as therapy, but for avoiding giving the hypoglycemia that may occur in which during D-ribose.If it is determined that There is not hypoglycemia when using D-ribose in concrete patient, then can get rid of D-Glucose.
Embodiment 1. the purest, the preparation of apyrogeneity ribose
The product prepared by fermentation is generally of some pyrogen residues, i.e. can induce heating when intravenous is used Material.Modal pyrogen contamination thing there is bacterial endotoxin.Therefore, use endotoxin analysis the most basic to measure material Upper apyrogeneity.Send out additionally, the undesirably by-product that produces the most during the fermentation of congener and heavy metal can keep and occur in In ferment product.
It is about by fermentation and the D-ribose prepared of purification 97% to 99% pure, and low-level endogenous toxin can be generally comprised Element.Although this product is safe for orally ingestible, and can be described as " food stage ", but it is not adapted for what intravenous was used " pharmaceutical grade ".D-ribose can be purified to pharmaceutical grade, and make its apyrogeneity.In brief, finally clean with pyrogen-free water And strictly cleaning all equipments, pyrogen-free water can be DDW or be prepared by reverse osmosis.All of solution and Reagent all uses apirogen water to prepare.Solution can carry out final sterilization step via ultrafiltration or autoclaving.
The ribose aqueous solution of preparation about 30% to 40%.Add activated carbon, and by suspension mixing at least 30 minutes, simultaneously Keep the temperature at 50-60 DEG C.Charcoal is filtered to remove.Filtered solution should be to clarify and almost colourless.Add ethanol To induce crystallization, and make crystal growth 1 day or 2 days.Process for convenience, grind this crystallization, and be transferred into rotating cylinder, bag Or in other container.One bag of desiccant is preferably provided to each container.End product is the purest, and without pyrogen, Heavy metal and congener.
The apyrogeneity D-ribose being suitable to intravenous use can be from Bioenergy, and Inc., Ham Lake, MN obtain.
Embodiment 2. to MI experimenter use D-ribose before result
A.Foker (U.S. Patent number 4,719,201) finds, after the normal body temperature phase of myocardial ischemia whole-heartedly of 20 minutes, Healthy dog heart needs up to rebuild normal baseline ATP level over 9 days.Use D-ribose during Reperfu-sion immediately and continue at least Within 4 days, strengthen ATP to recover.Whether design can be studied such as Foker Cardiac surgical procedures is postoperative with test human experimenter Healthy dog equally benefits from using of ribose, described experimenter or accept valve surgery and coronary artery bypass graft (CAB) (CABG) or individually CABG there is the cardiac function of reduction.
Recently, have studied the rat using ribose pretreatment to stand anterior MI.Find that some parameter of cardiac function obtains Significantly improve, including LV diastolic diameter, LV contracted diameter, ejection fraction and shortening fraction (shortening fraction).Before MI lures 14 days, use intravenous ribose.During and after not being reported in this program, ribose is executed With whether continuing (Befera, et al., J.Surg.Res.2007:137 (2): 156).As Befera has the MI of induction Shown in Healthy Youth rat, the early intervention that ribose is used may be adapted to the middle age suffering from AMI.
B. the Study on pretreatment carried out in being scheduled for operating human patients.
After FDA and Institutional Review Board (institutional review board) ratify, expected from registration Single centre, double blinding, 49 patients of placebo controlled clinical trial obtain Informed Consent Form, and this EXPERIMENTAL DESIGN is used for evaluating D-core The effect of the myocardial dysfunction that sugar is caused by the ischemia induced comprehensively in heart surgery for treatment.
Inclusive criteria is:
-the age is 18 years old or higher sex
The patient of the coronary artery disease with record of-experience CABG is super based on carry out within 8 weeks at surgical operation Sound kinetocardiogram, radionuclide imaging or cardiac catheterization, its ejection fraction (EF) is 35% (if employing one in the meantime Planting above method and evaluate EF, the meansigma methods of the most various methods is 35%).
The single prosthetic valve replacement of-experience or double valve replacement, the coronary artery disease with record and also acceptance The patient of CABG；Or only accept single prosthetic valve replacement or double valve replacement and do not accept the patient of CABG
-serum creatinine ＜ 2.35mg/dl
-for possible conceived women, pregnancy tests are negative.
-signature Informed Consent Form.
Experiment product, placebo or ribose are distributed to only accept the trouble of CABG by the random time table according to computer generation Person, or accept the patient of core valvular operation +/-CABG.All patients all receive high dose anesthetis anaesthesia technology, and it is by sweet smell Too Buddhist nun (50-100 μ g/kg) or sufentanil (10-20 μ g/kg) and midazolam forms.The anesthetis type used is not had Limit.Understanding and the generally acknowledged medical practice of patient demand are done by the anaesthetist and the surgeon that are responsible for care of patients based on them Go out clinical decision to support with use inotropic (inotropic) support, intraaortic balloon pump support or Coronary Artery Bypass Posterior circle, and Do not consider experiment product state.Starting intravenous experiment product infusion when aortic cross clamp and continue, moving until removing lung Arteries and veins catheter introducer or lasting 5 days (120 hours), no matter first which kind of situation occurs.It is responsible for the surgery of clinical care patient Doctor does not consider that experiment product state removes cardiopulmonary ductus arteriosus (pulmonary artery catheter cordis).
Obtain by heart rate, blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure (PCWP), central vein in following time interval Pressure (CVP) and the hemodynamic measurement that forms of thermodilution method cardiac index (CI): before induced anesthesia at once, after induced anesthesia Before the sternotomy, before after the sternotomy, cardiopulmonary bypass starts, cardiopulmonary bypass successfully terminate metasternum Guan Bi Before and use protamine to reverse before heparinization, after breastbone close, when arriving intensive care unit(ICU) and with 1 or 2 hour Interval is until removing pulmonary artery catheter.
Following time interval collect transesophageal echocardiography data (H.P.Sonos OR, 5.0MHz, Andover, MA): after induced anesthesia before the sternotomy and after breastbone close at once.Within the 3rd day and the 7th day during studying, carry out Transthoracic echocardiography (H.P.Sonos 1500.2.5MHz, Andover, MA) is measured.To transesophageal echocardiography with through breast For ultrasoundcardiogram, by area (mid-papillary in the middle of the acoustic quantification technique nipple to following major axis and short axle Area) change carry out three times measure: end-diastolicarea (EDA), end-systolicarea (ESA), Fractional areas change (FAC) ,+ DA/dt and-dA/dt.All area change data are analyzed also by artificial off-line analysis method.Also use long axis view determined off-line EF.Regional wall motion is carried out quantitatively additionally, as described below: normal=1, hypokinesia=2, move bad=3, with And the dyskinesia=4.Wall motion index scoring (WMIS) and normal myocardium percent is calculated by reading most 16 parts.Only When having seen from complete cardiac cycle the endocardial border more than 75%, just to surpassing for evaluating wall motion and area change Sound kinetocardiogram data are analyzed.Image View ultrasoundcardiogram work station (Nova Microsonics, Allendale, NJ) off-line analysis is carried out on.The transmural Doppler's flow-speed measurement carried out in mitral valve leaflet level include diastole early filling (E), Atrium fills composition (A) and E/A ratio.With nothing, trace, slight, moderate or severe is evaluated and quantitative valvular insufficiency.Right Treatment and result the most unclear explanation personnel analyze all of ultrasonic cardiography diagram data.
Record in 24 hours of experiment product and until all concomitant drugs of giving for 7 days, including indication, start time Between, end time and one or more accumulated dose.As available according to hospital's routine, to input (NG, oral and intravenous stream Body) and output (urine and other fluids) measure and record 7 days.
Clinical outcome parameters includes following: attempt breaking away from the number of CPB, extubation time, leaving the time of ICU, the time of leaving hospital Between, the application supported of the number of inotropic medicine and persistent period, intraaortic balloon pump and persistent period and Post operation 30 It survival.
After drugs infusion starts, the blood from intra-arterial catheters is used to pass through dextrastix (Accu- Chk III, Boehringer Mannheim Corp.Indianapolis IN) measure blood sugar level per hour.If blood glucose Remained stable 12 hours, then the blood sugar level after measuring for every 4-6 hour, until drugs infusion stops.At surgery Postoperative morning, complete other clinical laboratory measure, including with classification complete CBC, platelet count, electrolyte, Liver Function, Blood osmotic pressure and urinalysis.Repeat abnormal laboratory to test as clinical indication, until normal or Determine that not there is clinical meaning.
By all data input Microsoft Excel Spreadsheet (v4.0, Microsoft Corp., Redmond, WA).Solve blind before, examine the ultrasonic cardiography diagram data of 100%, the hemodynamic data of 20% and 5% Every other data.Error rate for input is less than 0.001%.Before this research solution is blind, formulate detailed statistical analysis plan, use In evaluating the most reliable and effective data of population.At JMP software (for the v3.1 of Windows, SAS Institute Inc., Cary, N.C.) all statistics of upper calculating.This plan eliminates those and is considered to evaluate due to violation scheme Patient, including interrupt experiments product use more than 4 hours (experimenter), the most limited ultrasoundcardiogram test, with And unrelated operation room (interoperative) operation difficulty (two experimenters) is processed with pharmacology.Covariant include the age, Aortic cross clamp time, baseline EF and baseline WMIS.Statistics experiment includes that card side, t check, for repeated measures The univariate analysis of variance (ANOVA) and covariance analysis (ANCOVA).For all statistical test, p ＜ 0.05 (bilateral) It is considered to represent significance,statistical.
After including 49 patients in, suspending the registration of other patients, this is owing to following mechanism determines (institutional decision): after surgery to all patients undergoing cardiac valve replacement tube drawings and in 24 hours in 6 hours Patient is made to leave ICU, if stable clinically.This decision needs to change anaesthesia technology and post surgery treatment.As the most final The only result of research, we eliminate 9 registration patients from analyze, including suffer from isolated mitral incompetence (n=3), Isolated mitral stenosis (n=3), the aorta merged and those patients of mitral valve disease (n=3).
Checking demography and the base line measurement of following patient's cardiac function, described patient is that those pass through ultrasonic cardiography Figure can determine that baseline EF and the patient of 7 days EF, and suffers from the patient (n=27) of aortic stenosis or coronary artery disease.With The patient of placebo treatment compares, and the patient age that ribose processes is bigger (66.5 years old ratio 56.4 years old, p=0.026), and often There is relatively low baseline EF.But, the baseline differences of EF is not reaching to statistical significance.These patients are not found yet, and other show The baseline differences write.
At the 7th day, the patient average baselining EF of placebo treatment was dropped to 38% (p=0.0025) by 55%.At ribose The average baselining EF and 7 days EF of the patient of reason are not changed in (44% to 41%, p=0.49).The process group split plot to EF (split plot) time effect has significant difference (prob ＞ F, p=0.04), as used the repetition for chance mechanism The univariate analysis of variance model measured calculates.In the patient that ribose processes, EF is maintained, and in placebo treatment In patient, EF declines.The hypothesis test that JMP provides is consistent with the hypothesis test of SAS-PROC GLM (Group III and IV class).
There is hypoglycemia (fingerstick glucose ＜ 70mg/dl) in 5 patients's (28%) in ribose process group, this is this The known side effect of pentose.There is not hypoglycemia in the patient of placebo treatment.Occur in those patients hypoglycemic is average Glucose level is 58mg/dl.Minimum glucose level is 31mg/dl.Three experimenters use and inject D50W process；One Experimenter uses oral Sucus Mali pumilae to process；One experimenter need not process.Due to hypoglycemia, stop grinding in two experimenters Study carefully infusion of drug.The most there is not neurological or other clinical symptoms relevant with hypoglycemia in these patients.Other is clinical Laboratory measurement does not has significant difference.It is important to note that, runs counter to the analysis including the experimenter of scheme include those Do not change any statistical result.
This test shows that the D-ribose infusion in the patient with CABG, under 100mg/kg/hr is to Post operation EF's The potential benefit kept.Infusion by than research Orally administered more effectively because its can be continuous rather than be interrupted, and And can be administered to can not pickuping food or the patient of liquid.Under study for action, in the patient of placebo treatment, EF drops from baseline Low, and EF is maintained in the patient that ribose processes.Although it should be noted that use standard method carries out randomization, but In this people group, the patient accepting ribose has lower EF.But, EF is maintained, and placebo is higher simultaneously EF reduces.
The scheme that embodiment 3. metabolism is guided
After the preliminary study described in example 2, have registered 366 companies in the 41-88 year experiencing OPCABG Continuous patient.Wherein, 89 suffer from MIs recently, and 7 occurred in that MIs in 1 to 7 day.The data that expection is collected include concurrently Disease, hematodinamics and result.Use all patients of project management emphasizing that blood glucose amount is normal, body temperature normal and inflammation reduces. Group 1 (n=308) accepts repeatedly the D-ribose of oral dose (5 grams/dosage) before surgical operation and after surgical operation.Group 2 (n=58) with identical metabolism project management, but D-ribose is not accepted.Group 2 more likely experiences sudden OPCABG (9% ratio 1%, p0.001), but group 1 has cardiac index (CI sees table 1) before relatively harmonic(-)mean surgical operation.It addition, two groups all have class As feature before surgical operation, including ejection fraction (EJ) and breast surgery association (Society for Thoracic Surgery, STS) risk index, the trend that in group 1, complication increases is the most notable.
Group 1 trends towards time of Intensive Care Therapy less when little (72 to 87), and relatively low (12% compares for the requirement of IABP 21%), but these trend are not significances.Although preoperative CI is poor, but group 1 trends towards higher Post operation CI, and it is bigger (0.8 to 0.4, p ＜ 0.001) to organize the increase after 1 surgery.Additionally, after OPCABG, Group 1 in 86% prove CI increase, but group 2 in only 66% have CI increase (p ＜ 0.001).There are three example peri-operation period MIs, Not having apoplexy, two patients need hemodialysis, and there is an example Post operation dead (group 1).
Table 1
Suffering from altofrequency related complication, including in the patient of Left main artery disease and nearest MI, the program and OPCABG The most challenging result is correlated with.Although experience is initial or repeats (n=5% in n=7%, and group 2 in group 1) Before surgical operation in group 1 patient of OPCABG, CI is the lowest, but these patients accepting D-ribose actually prove relatively Good surgical site infections CI, hint cardiac muscle recovers to strengthen.This research is not random in terms of adding D-ribose, but we Result implies, the randomized prospective test using D-ribose is card to the advantageous effect using D-ribose after studying MI further Bright reasonably.Especially, the most useful include that by being the patient's intravenous to suffering from MI uses D-ribose.Expection is due to some MI Patient may not absorb oral D-ribose, and intravenous is used for suffering the patient of nearest MI to provide more benefit.
Embodiment 4. uses D-ribose under hospital care is permitted
Although A. these researchs are likely, but the most do not replicate patient and go out with acute myocardial infarction under the first reaction Existing clinical setting, now the time is important.In most cases, MI is proactive case, but at process such as angiography MI can be induced during art, angioplasty or Dobutamine Stress Echocardiography imaging.Such patient is typically in heart merit During damaging.Table II shows 7 acute, the first reaction MI patients and described below as Table I all patients, employing The comparison of 308 patients of D-ribose pretreatment.
Table II
The comparison of whole D-ribose patients of the first reaction MI patient and Table I
Age Operation consent CI Post operation CI Change
The group 1 of Table I 70±11 2.3±0.5 3.0±0.7 +0.07
First reaction 74.7±5 2.19±0.7 2.60±0.4 +0.41
Notice that these first reaction patients are in after experience MI during heart damage, and use in D-ribose Only this infringement, as in the Table I patient (group 2) by not using D-ribose, CI continuation reduces visible.It should also be mentioned that this 7 Name patient is included in the group 1 of Table I.Compared with whole groups, by preload D-ribose, they can keep and somewhat increase it CI。
First response procedures of standard includes administration of oxygen, aspirin and vasodilator immediately, arranges venous access (clot busting) is smashed with grumeleuse.Embodiment 2 confirms: compared with using D-Glucose, during cross clamp aorta Intravenous is used D-ribose holding and improves EF afterwards；Before MI or CABG of induction, it is favourable with D-ribose pretreatment 's.Table II confirms, D-ribose joins the standard first of acute MI patient when reacting in nursing, and early intervention is the most oral Use and can significantly decrease heart damage.
B. clinical research.Single centre, clinical trial design random, double-blind placebo-controlled comparison are used for determining in hospital care Use under license whether D-ribose can improve the functional parameter of heart.Can pickuping food and water by Orally administered for D-ribose giving Those patients and intravenous be administered to can not pickuping food and those patients of water.The intravenous dosages of D-ribose be 30 to 300mg/kg/ hour, the aqueous solution of the apyrogeneity D-ribose of 5 to 30%w/v deliver.When in time jointly using D-Glucose, It can be delivered by the aqueous solution of the D-Glucose of 5 to 30%w/v.D-ribose is tapped into venous access, and flowing is set as Deliver 30 to 300mg/kg/ hour.In many research, find 100 to 200mg/kg/ hour for maximum D-ribose benefit Place is enough.When Orally administered possibility, the D-ribose of 1 to 20 gram is blended in the water of 200ml, and every day absorbs 1 To 4 times.In many research, found that it is enough for absorbing 3 or 4 D-riboses of 5 grams every day.For executing for intravenous The practicality of apyrogeneity D-ribose, the stable and prevention of the heart damage seen in Table II is for occurring in hospital or clinic It is available for the unconscious of the first reaction or vomiting patient.
The parameter of research will there be infarct size and marginal zone (border zone) size.

Claims (5)

1. the D-ribose of effective dose suffers from patient's cardiac of acute myocardial infarction in preparation for the first reaction nursing with prevention Application in the medicine of infringement, the cardiac index of wherein said patient is maintained or improves.
2. the application of claim 1, wherein can pickuping food and the trouble of water by Orally administered for the D-ribose of described effective dose giving Person and intravenous are administered to can not pickuping food and the patient of water.
3. the application of claim 2, wherein treats the D-ribose that D-ribose is 2 to 5 grams of Orally administered described effective dose, described D-ribose daily 1 to four time.
4. the application of claim 2, wherein treats that the effective dose of the described D-ribose that intravenous uses is that 50 to 300mg/kg/ is little Time, and described D-ribose is pyrogen-free.
5. the application of claim 1, wherein said medicine is used in combination with the oxygen of aspirin, Sublingual nitrate and suction.
CN201610602300.6A 2008-04-02 2009-04-02 Ribose is for the purposes in the first reaction of acute myocardial infarction Pending CN106138071A (en)

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CA2757442A1 (en) 2009-10-08
CN102387805A (en) 2012-03-21
US20200206252A1 (en) 2020-07-02
EP2413942A1 (en) 2012-02-08
US20170326165A1 (en) 2017-11-16

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